DESCRIPTION (from the application): Historically, limb lengthening procedures have suffered by failure or delay of regenerating bone to bridge the lengthening gap. Since the introduction of distraction osteogenesis (DO) by G.A. Ilizarov in 1951, bone formation by this method has significantly improved care of patients with limb deficiencies from congenital and post-traumatic conditions. DO is a variant of fracture healing that stretches the biological process to its natural limits. Clinically and experimentally, investigators have determined that the process breaks down with aging, in a similar fashion to the generalized failure of bone formation found in age-related osteoporosis. Patients with fracture healing problems are more prevalent than the patients requiring limb lengthening; however, bone formation by DO may hold a key to understanding how to improve bone formation during aging. Preliminary studies have demonstrated that 1) DO in aged rats is characterized by a dramatic deficiency in endosteal (not periosteal) bone formation, 2) fibroblast growth factor-2 (FGF-2) is expressed during DO at the mRNA level specifically in developing bone and sinusoid cells, and 3) systemic administration of rhFGF-2 to old rats partially restores endosteal bone formation. The aims of this proposal are 1) to modulate, during DO and non-distracted fracture (NDFX) healing, the local activity of FGF-2 and to determine the effects on bone formation in young and old rats, and 2) to explore the mechanisms underlying the FGF-2 effects. Bone formation and quality will be monitored by radiography, histology, immunocytochemistry, in situ hybridization, tensile tests, and three point bending. The long term goals of this proposal are 1) to uncover the mechanisms underlying DO, including regulation of the cellular phenotypes and stage-specific genes and 2) to develop protocols for enhanced bone formation during limb lengthening and fracture healing with the focus on delayed and non-unions in pediatric to geriatric patients.